By: Natalie L. Boehm, MBA, RBLP-T
What is Periventricular Heterotopia?
Periventricular heterotopia, also known as periventricular nodular heterotopia, is a condition in which nerve cells do not migrate properly during the early development of the fetal brain (GARD, 2021).
Causes
Periventricular heterotopia is caused by malfunctioning of one of more of the following genes: ARFGEF2, FLNA, ERMARD, NEDD4L, TMTC3, ARF1, AND MAP1B.
ARFGEF 2: The ARFGEF 2 gene is responsible for providing the information for making protein that helps with the movement of small sac-like structures (vesicles) within the cell. The ARFGEF 2 protein then converts a molecule called guanine diphosphate (GDP) then to another molecule called guanine triphosphate (GTP) (Medline Plus, 2007).
FLNA: the FLNA gene is responsible for producing the protein filamin A, which helps to build cells extensive internal network of protein filaments called the cytoskeleton. The cytoskeleton give structure to the cells and allow them the flexibility to change shape (Medline Plus, 2022). Filamin A is also involved in the organization of the extracellular matrix, binding to proteins called integrins, which span the cell membrane and anchor cells to the extracellular matrix (Medline Plus, 2022).
ERMARD: the ERMARD gene is located in the endoplasmic reticulum and may be involved in neuronal migration (National Center for Biotechnology Information, 2022).
NEDD4L: NEDD4L helps to encode HECT domain E3 ubiquitin ligases, converting them to protein substrates, targeting specific proteins for lysosomal degradation. The encoded protein plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel ENaC (National Center for Biotechnology Information, 2022).
TMTC3: TMTC3 is a gene that encodes a protein that belongs to the transmembrane and tetratricopeptide repeat-containing protein family (National Center for Biotechnology Information, 2022).
ARF1: ARF1 is a member of the human ARF gene family, encoding small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase and play a role in vesicular trafficking as activators of phospholipase D. ARF 1 is located in the Golgi apparatus and has a central role in intra-Golgi transport (National Center for Biotechnology Information, 2023).
MAP1B: the MAP1B gene encodes a protein that belongs to the microtubule-associated protein family, which are thought to be involved in microtubule assembly. Studies have shown that the protein 1B gene plays an important role in the development and function of the nervous system (National Center for Biotechnology Information).
Diagnosis
According to McGovern Medical School at the University of Texas at Houston, an MRI is first ordered. If there are abnormalities in the grey matter nodules, resulting them to bulge into the ventricular walls, the neurologist may order a PET scan to confirm diagnoses or examine the patient for related conditions.
Signs and Symptoms
The first signs of periventricular heterotopia is when seizure activity starts to take place. According to the Genetic and Rare Diseases Information Center at the National Institute of Health, the following symptoms are associated with periventricular heterotopia:
- Abnormal bleeding (also known as bleeding diathesis, may be related to vascular, platelet, and coagulation defects)
- Gastroesophageal reflux (condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter)
- Hernia
- Pyloric stenosis (also known as infantile hypertrophic pyloric stenosis, an uncommon condition in infants characterized by abnormal thickening of the pylorus muscles in the stomach, leading to gastric outlet obstruction)
- Scoliosis (abnormal lateral curvature of the spine)
- Abnormal heart valve morphology (any structural abnormality of a cardiac valve)
- Abnormal nervous system morphology (structural anomaly of the nervous system)
- Aortic regurgitation (an insufficiency of the aortic valve, leading to regurgitation (backward flow) of blood from the aorta into the left ventricle)
- Focal-onset seizure (originates within networks limited to one hemisphere)
- Joint hypermobility (ability of a joint to move beyond its normal range of motion)
- Patent ductus arteriosus
- Periventricular heterotopia (mislocalized gray matter is typically located periventricularly, also called subependymal heterotopia. Can be a small single node or a large number of nodes. Can be on both sides of the brain)
- Thin skin (generally associated with a loss of suppleness and elasticity of the skin)
- Aortic aneurysm (localized dilation the aorta that is more than 150 percent)
- Patellar dislocation (dislocation of the kneecap)
- Shoulder dislocation (displacement/misalignment of the humerus to the other bones of the shoulder joint)
Treatment
According to the Epilepsy Foundation, the following treatments are available for patients with periventricular heterotopia:
Medication:
Oxcarbazepine (Trileptal)
Carbamazepine (Tegretol or Carbatrol)
Levetiracetam (Keppra)
Topiramate (Topamax)
Zonisamide (Zonegran)
Lacosamide (Vimpat)
Other treatments:
Surgery (for drug-resistant seizures)
Laser interstitial thermal therapy (LITT)
Keto diet, Modified Atkins diet, low glycemic index diet
VNS, RNS, DBS
(Alwaki and Danoun, Epilepsy Foundation, 2021)
Conclusion
Periventricular Heterotopia, also known as periventricular nodular heterotopia, is a condition in which nerve cells do not migrate properly during the early development of the fetal brain. Periventricular heterotopia is caused by genetic malfunctioning of one or more of the genes ARFGEF2, FLNA, ERMARD, NEDD4L, TMTC3, ARF1, AND MAP1B. There are many symptoms that someone with periventricular heterotopia can experience. Medication, surgery, dietary, and devices are all treatment options for people with periventricular heterotopia
Resources:
Alwaki, A. and Danoun, O. (2021). Periventricular Nodular Heterotopias (PVNH). Epilepsy Foundation. Retrieved from: https://www.epilepsy.com/causes/structural/periventricular-nodular-heterotopias-pvnh
Genetic and Rare Diseases Information Center (GARD) (2021). Periventricular heterotopia. National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center. Retrieved from: https://rarediseases.info.nih.gov/diseases/12724/periventricular-heterotopia
Medline Plus (2007). ARFGEF 2 gene, ADP ribosylation factor guanine nucleotide exchange factor 2. National Library of Medicine. Retrieved from: https://medlineplus.gov/genetics/gene/arfgef2/
Medline Plus (2022). FLNA gene, filamin A. National Library of Medicine. Retrieved from: https://medlineplus.gov/genetics/gene/flna/
National Center for Biotechnology Information (2023). ARF 1 ADP ribosylation factor 1 [Homo sapiens (human)]. National Library of Medicine. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/375
National Center for Biotechnology Information (2022). ERMARD ER membrane associated RNA degradation [Homo sapiens (human)]. National Library of Medicine. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/55780
National Center for Biotechnology Information (2022). MAP1B microtubule associated protein 1B [Homo sapiens (human)]. National Library of Medicine. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/4131
National Center for Biotechnology Information (2022). NEDD4L NEDD4 like E3 ubiquitin protein ligase [Homo sapiens (human)]. National Library of Medicine. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/23327
National Center for Biotechnology Information (2022). TMTC3 transmembrane O-mannosyltransferase targeting cadherins 3 [Homo sapiens (human)]. National Library of Medicine. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/160418
UT Health Houston Neurosciences (n.d.). Periventricular Nodular Heterotopia. UT Health Houston Neurosciences, McGovern Medical School. Retrieved from: https://med.uth.edu/neurosciences/periventricular-nodular-heterotopia/
